Abstract IA017: Metabolic reprogramming and kidney cancer progression

Abstract

Many human diseases, including cancer, involve alterations of cellular metabolism caused either directly or indirectly by mutations in genes that regulate the metabolic network. In cancer, reprogrammed metabolic activities arising from mutations in tumor suppressors and oncogenes are thought to contribute both to cancer initiation and progression, particularly metastasis. In clear cell renal cell carcinoma, as with many other kinds of cancer, mortality is largely dictated by metastatic dissemination. It is therefore of interest to identify aspects of metabolic reprogramming that promote metastasis in ccRCC patients. We used a multidisciplinary clinical approach to infuse 13C-labeled nutrients during surgical tumor resection in ccRCC patients. Compared to the adjacent kidney, ccRCCs displayed suppressed labelling of tricarboxylic acid (TCA) cycle intermediates, both in vivo and in organotypic slices cultured ex vivo, indicating that suppressed labeling is a tissue intrinsic property of these tumors. Infusions of 13C-acetate and 13C-glutamine in patients, coupled with metabolic analysis of mitochondria isolated from kidney and tumor tissue, revealed primary defects in mitochondrial function in human ccRCC. However, ccRCC metastases unexpectedly had enhanced labeling of TCA cycle intermediates compared to primary ccRCCs, indicating a divergent metabolic program during ccRCC metastasis in patients. Using a syngeneic RCC mouse model capable of spontaneous metastasis from the kidney, we found that inhibiting oxidative phosphorylation reduced metastasis to the lung without impacting tumor growth in the kidney. In human ccRCC cells, stimulating respiration was sufficient to promote metastatic colonization in the lung. Altogether, these findings indicate that metabolic properties evolve during human ccRCC progression, and suggest that mitochondrial respiration may be limiting for ccRCC metastasis but not for ccRCC growth at the site of origin.

Citation Format: Ralph J. DeBerardinis. Metabolic reprogramming and kidney cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA017.